step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp² carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally result in an essentially irreversible inhibition of HDAC6.22:T446,Using a microwave-assisted protocol, we synthesized 16 peptoid-capped HDAC inhibitors (HDACi) with fluorinated linkers and identified two hit compounds. In biochemical and cellular assays, 10h stood out as a potent unselective HDACi with remarkable cytotoxic potential against different therapy-resistant leukemia cell lines. 10h demonstrated prominent antileukemic activity with low cytotoxic activity toward healthy cells. Moreover, 10h exhibited synergistic interactions with the DNA methyltransferase inhibitor decitabine in AML cell lines. The comparison of crystal structures of HDAC6 complexes with 10h and its nonfluorinated counterpart revealed a similar occupation of the L1 loop pocket but slight differences in zinc coordination. The substitution pattern of the acyl residue turned out to be crucial in terms of isoform selectivity. The introduction of an isopropyl group onto the phenyl ring provided the highly HDAC6-selective inhibitor 10p, which demonstrated moderate synergy with decitabine and exceeded the HDAC6 selectivity of tubastatin A.23:T405,Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastoma and glioblastoma. In this work, we have rationally designed a novel class of peptoid-based histone deacetylase inhibitors (HDACi). A mini library of β-peptoid-capped HDACi was synthesized using a four-step protocol. All compounds were screened in biochemical assays for their inhibition of HDAC1 and HDAC6 and docking studies were performed to rationalize the observed selectivity profile. The synthesized compounds were further examined for tumor cell-inhibitory activity against a panel of neuroblastoma and glioblastoma cell lines. In particular, non-selective compounds with potent activity against HDAC1 and HDAC6 showed strong antiproliferative effects. The most promising HDACi, compound 6i, displayed submicromolar tumor cell-inhibitory potential (IC₅₀: 0.21-0.67 μM) against all five cancer cell lines investigated and exceeded the activity of the FDA-approved HDACi vorinostat.

	Year	Citations

About